Hypervolemic shock followed by resuscitation represents a systemic ischemia/reperfusion injury, and often leads to acute lung injury manifested as the Adult Respiratory Distress Syndrome (ARDS). Although the complex series of inflammatory events that lead to the development of ARDS have not been completely determined, cytokines and neutrophils have been implicated as effectors of the increase in pulmonary microvascular permeability that characterizes this syndrome. The Kupffer cells of the liver represent the largest fixed macrophage population in the body, giving the liver a significant capacity for macrophage-dependent cytokine production and release. Clinically, the liver is highly susceptible to hypovolemic shock. Tumor necrosis factor-alpha (TNF) is an early response cytokine that is produced in the context of hepatic ischemia/reperfusion injury and plays a significant role in the ensuing acute lung injury. This lung injury is characterized by neutrophil influx and increased pulmonary microvascular permeability. Cytokines released from the liver during hypovolemic shock and resuscitation (ischemia/reperfusion injury), or following reimplantation of an orthotopically transplanted liver, may play a role in the pathogenesis of ARDS. Our hypothesis for neutrophil recruitment and extravasation into the lung following reperfusion of an ischemic liver, with resultant acute pulmonary microvascular injury is as follows: hepatic reperfusion precipitates TNF release into the hepatic venous circulation. This system empties directly into the pulmonary microvasculature, causing TNF-mediated upregulation of pulmonary endothelial expression of ICAM-1. TNF concurrently mediates the local pulmonary generation of neutrophil chemotactic cytokines, such as ENA-78, resulting in neutrophil chemotaxis, activation within the intravascular compartment, and upregulation of neutrophil-derived beta-2 integrin adhesion molecules. The subsequent interaction of beta-2 integrin with its receptor/ligand, ICAM-1, results in neutrophil-endothelial adhesion. The next steps leading to neutrophil diapedesis and migration beyond the vascular compartment may be dependent upon both continued expression of beta-2 integrins and movement along a neutrophil-specific (ENA-78) chemotactic concentration gradient. These events precipitate an influx of neutrophils into the pulmonary interstitium, resulting in neutrophil- mediated lung injury, manifested as increased microvascular permeability, tissue injury, and organ dysfunction. This application will specifically address TNF-induced expression and regulation of pulmonary endothelial cell ICAM-1 and pulmonary-derived ENA-78, in addition to assessing the direct effects of ICAM-1 and ENA-78, in the pathogenesis of hepatic ischemia/reperfusion-induced pulmonary injury. This investigation will focus on the impact of an isolated liver in on the lung, facilitating evaluation of the mechanistic role of hepatic-derived cytokines in the pathogenesis of ARDS and the role that these cytokines play in neutrophil activation and recruitment in to the lung.